Abstract

(1S,2S,3S,4R,5S)-5-[4-Chloro-3-(4-ethoxybenzyl)phenyl]-1-hydroxymethyl-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triol (PF-04971729), a potent and selective inhibitor of the sodium-dependent glucose cotransporter 2 (SGLT2), is currently in phase 2 trials for the treatment of diabetes mellitus. The paper describes the preclinical species and in vitro human disposition characteristics of PF-04971729, which were performed to support the first-in-human study. Plasma clearance was low in rats (4.04 ml/min/kg) and dogs (1.64 ml/min/kg) resulting in half-lives of 4.10 hours and 7.63 hours, respectively. Moderate to good bioavailability in rats (69 %) and dogs (94 %) was observed after oral dosing. The in vitro biotransformation profile of PF-04971729 in liver microsomes and cryopreserved hepatocytes from rat, dog and human was qualitatively similar; prominent metabolic pathways included mono-hydroxylation, O-deethylation and glucuronidation. No human-specific metabolites of PF-04971729 were detected in in vitro studies. Reaction phenotyping studies using recombinant enzymes indicated a role of CYP3A4/3A5, CYP2D6 and UGT1A9/2B7 in the metabolism of PF-04971729. No competitive or time-dependent inhibition of the major human cytochrome P450 enzymes was discerned with PF-04971729. Inhibitory effects against the organic cation transporter 2 mediated uptake of [¹⁴C]-metformin by PF-04971729 also were very weak (IC₅₀ ~ 900μM). Single-species allometric scaling of rat pharmacokinetics of PF-04971729 was used to predict human clearance, distribution volume and oral bioavailability. Human pharmacokinetic predictions were consistent with the potential for a low daily dose. First-in-human studies following oral administration indicated that the human pharmacokinetics/dose predictions for PF-04971729 were in the range that is likely to yield a favorable pharmacodynamic response.